Viral infection and the evolution of caspase 8-regulated apoptotic and necrotic death pathways

Key Points Apoptosis and programmed necrosis are common host defence signalling pathways that contribute to the elimination of intracellular pathogens. Caspase 8 promotes apoptosis and suppresses programmed necrosis in complex with FAS-associated death domain protein (FADD) and cellular FLICE-like inhibitory protein (cFLIP). Many viruses encode inhibitors of caspase 8 activity to suppress apoptosis. Caspase 8 inhibition unveils programmed necrosis, a pathway that may also be suppressed by viral inhibitors of cell death. Programmed necrosis has only recently been recognized as a host-defence pathway through the characterization of cell death suppressors encoded by murine cytomegalovirus (MCMV). Programmed necrosis is dependent on receptor-interacting protein 3 (RIP3) and can be either RIP1-dependent (necroptosis) or RIP1-independent (MCMV-induced programmed necrosis). Pathogen-associated dysregulation of caspase 8 can drive both inflammation and programmed necrosis, contributing to disease outcomes. Programmed cell death of infected host cells builds up the first line of defence against viruses. Here, Mocarski and colleagues describe the tight regulation of caspase 8-dependent apoptosis and programmed necrosis and discuss how viral inhibitors of cell death may have contributed to the evolution of programmed necrosis to promote host survival. Pathogens specifically target both the caspase 8-dependent apoptotic cell death pathway and the necrotic cell death pathway that is dependent on receptor-interacting protein 1 (RIP1; also known as RIPK1) and RIP3 (also known as RIPK3). The fundamental co-regulation of these two cell death pathways emerged when the midgestational death of mice deficient in FAS-associated death domain protein (FADD) or caspase 8 was reversed by elimination of RIP1 or RIP3, indicating a far more entwined relationship than previously appreciated. Thus, mammals require caspase 8 activity during embryogenesis to suppress the kinases RIP1 and RIP3 as part of the dialogue between two distinct cell death processes that together fulfil reinforcing roles in the host defence against intracellular pathogens such as herpesviruses.